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EP0452697B1 - Stabilizer for 4-ethyl-2-hydroxyimino5-nitro-3-hexenamide-containing preparation and stabilizing method therefor - Google Patents

Stabilizer for 4-ethyl-2-hydroxyimino5-nitro-3-hexenamide-containing preparation and stabilizing method therefor Download PDF

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Publication number
EP0452697B1
EP0452697B1 EP91104502A EP91104502A EP0452697B1 EP 0452697 B1 EP0452697 B1 EP 0452697B1 EP 91104502 A EP91104502 A EP 91104502A EP 91104502 A EP91104502 A EP 91104502A EP 0452697 B1 EP0452697 B1 EP 0452697B1
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Prior art keywords
stabilizer
acid
drug
hexenamide
nitro
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German (de)
French (fr)
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EP0452697A1 (en
Inventor
Yoshio Ueda
Norio Onishi
Mitsuru Yasumura
Kazuto. Rm 106 Rohderu Crt Esta Gakuenmae Okimoto
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a use of a stabilizer for 4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide represented by the following chemical formula (I), in particular, ( ⁇ )-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide or a salt thereof acceptable as drug or drugs containing as pharmacologically active ingredient the above compound, and a stabilizing method by the use thereof.
  • a stabilizer for 4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide represented by the following chemical formula (I), in particular, ( ⁇ )-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide or a salt thereof acceptable as drug or drugs containing as pharmacologically active ingredient the above compound, and a stabilizing method by the use thereof.
  • FK409 is poor in stability and when, for instance, it is left standing at 40 °C for 2 months, it is completely decomposed to a dark brown fused substance with its pharmacological activity lost.
  • the present invention has been made for improvement in this respect and is aimed at provision of a use of a stabilizer effective for preventing decomposition of FK409 and having its pharmacological activity kept for a long period.
  • Another object of the present invention is provision of a method of stabilizing FK409 or drugs containing it as the pharmacologically active ingredient.
  • JP-A-60-28923 discloses an organic acid (e.g. stearic acid, palmitic acid, citric acid, tartaric acid etc.) as a stabilizer in a pharmaceutical composition applicable to the oral mucosa.
  • organic acid e.g. stearic acid, palmitic acid, citric acid, tartaric acid etc.
  • FR-A-2 333 494 discloses a process for stabilising a solution of a derivate of pyrido(3, 2-a)phenoxazine in which ascorbic acid and isoascorbic acid is used as a stabilizer.
  • the stabilizer used according to the present invention is characterized in that it comprises one or more of organic acids selected from tartaric acid, stearic acid, ascorbic acid, erythorbic acid and malonic acid and the method of the invention is characterized in that stabilization is attained by mixing the aforementioned stabilizer in drugs containing FK409, and the stability of FK409 as a pharmacological ingredient is markedly improved and FK409-containing drugs excelled in durability of activity are obtained.
  • the present inventors studied various compounds to see their stabilizing effect, that is, to see if they are effective for preventing decomposition of FK409, and as a result discovered that compounds selected from organic acids selected from tartaric acid, stearic acid ascorbic acid, erythorbic acid and malonic acid have excellent stabilization effect.
  • compounds selected from organic acids selected from tartaric acid, stearic acid ascorbic acid, erythorbic acid and malonic acid have excellent stabilization effect.
  • the above exemplified polycarboxylic acid has an asymmetric carbon atom(s) such as tartaric acid, or malonic acid
  • each of D-form, L-form or racemic mixture may be used.
  • the salt of FK409 may be pharmaceutically acceptable salt including organic or inorganic salt.
  • the quantity of the aforementioned compound to be added as stabilizer there is no limitation but it is preferred to be not less than 0.1 weight part, more preferably in a range of 0.3-5 weight part, of the quantity of FK409.
  • the drug composition of the present invention can be mixed with organic or inorganic carriers or excipients suited for external, oral or non-oral administration so as to be usable as solid, semisolid or liquid medical preparations containing the effective substance of the invention.
  • the invented effective substance may be mixed with any of the ordinary, nontoxic carriers permitted for medical use and suited for preparation of tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and the like.
  • Such carriers may be cited water, dextrose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium silicate, talc, corn starch, keratin, colloid silica, potato starch and urea in solid, semisolid or liquid form, being suited for drug manufacture, and auxiliaries, stabilizers, thickeners, colorants and aromatics are also usable. It is also possible to use preservatives or bacteriostats for stably maintaining the activity of the drug or its effective ingredient in any given form.
  • the medical composition of the invention is also usable for manufacture of persistent drugs of various forms. It is also possible to use the aforementioned drugs as long lasting drugs of various forms.
  • FK409 is poor in stability when mixed with an excipient for drug manufacture and its activity is lost quickly when the mixture is kept in stock at a high temperature, but its decomposition is markedly prevented when one of the aforementioned compounds is added as stabilizer for the resultant preparation or drug to be highly improved in durability of pharmacological activity.
  • the FK409 content of a drug of the present invention may be determined properly with the stage of the disease the drug is prescribed for and its form, if the desired therapeutic effect could be attained.
  • the drug of the invention may be prepared in various forms suited for venous or muscular injection, cutaneous administration as in the case of plaster or suppository or oral administration.
  • the dosage depends on the stage of disease and the age of the patient but, generally, the effective dose of FK409 is approx. 0.1-100 mg/kg a day and normal per-time dose is 10 mg, 50 mg, 100 mg or 250 mg on the average.
  • composition and effect of the drug of the present invention will be specifically described below with reference to the cited example.
  • compositions of the individual samples are shown in Table 1 and the results in Table 2.
  • FK409 either in the form of original powder (recipe No. 1) or mixed with an excipient (recipe No.2), totally loses its pharmacological activity after storage for 1 month at 40 °C , but when a proper dose of tartaric acid is added (as stabilizer), decomposition of FK409 is markedly prevented and its residual percentage is largely increased.
  • Table 3 below is given to show the result of study about various compounds on their stabilizing effect on the original powder of FK409.
  • Stabilizer dose(g) Storage condition and residual (%) 40 °C 50 °C 60°C 60°C 1 month 1 month 18 days 7 days FK409 Original powder - 0 0 0 99.3 DL-Tartaric acid 1 97.2 98.0 88.1 99.0 Stearic acid 1 99.3 95.2 - - Vitamin C 1 97.1 98.3 87.8 99.0 Erythorbic acid 1 96.3 98.4 83.5 99.8 DL-Malonic acid 1 98.9 83.5 32.5 90.1 DL-citric acid anhydride 1 70.1 76.3 - -
  • the dose of stabilizer in g is per 1 g of the original powder of FK409.
  • the ingredients in the recipe shown Table 4 except only magnesium stearate were mixed, 40 ml of water was added to the mixture (approx. 135 g) and the wetted mixture was uniformly kneaded, vacuum dried and granulated. To the granules the prescribed amount of magnesium stearate was added and, after mixing, the mixture was made into tablets 7mm in diameter by the use of a tablet making machine.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

A stabilizer for 4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide represented by the following chemical formula (I) or a salt thereof acceptable as drug or drug containing as pharmacologically active ingredient a compound represented by a chemical formula (I) , in particular, (+/- )-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide or salt/s thereof acceptable as drugs, a stabilizing method by the use thereof and drugs containing such stabilizer and stabilized thereby. <CHEM> s

Description

    BACKGROUND OF THE INVENTION Field of the Invention
  • The present invention relates to a use of a stabilizer for 4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide represented by the following chemical formula (I), in particular, (± )-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide or a salt thereof acceptable as drug or drugs containing as pharmacologically active ingredient the above compound, and a stabilizing method by the use thereof.
    Figure imgb0001
    • Description of the Prior Art
  • It is well know from Japanese Laid-open Patent Publication No. 59-152366 that (E)-4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide or its salt/s accepted as drug has pharmacological activity as a vasodilating drug, anti-thrombotic drug, drug for angina pectoris or the like and, it is disclosed in the aforementioned publication that this compound can be manufactured as drugs in form of tablet, capsule, pellet, suppository and the like and that various excipients can be used in the manufacture thereof. Through further studies it has been confirmed that the aforementioned compound, in particular, (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide or a salt thereof has a excellent pharmacological activity. Since this compound is called FK409 by this applicant and about it clinical studies are now under way, the compound to be stabilized by the method of the present invention will hereinafter be represented by this name.
    • SUMMARY OF THE INVENTION
  • FK409 is poor in stability and when, for instance, it is left standing at 40 °C for 2 months, it is completely decomposed to a dark brown fused substance with its pharmacological activity lost. For manufacture of drugs in some of the aforementioned forms it has to be mixed with proper excipients but when mixed with an excipient, it is extremely poor in stability and the content of the active ingredient is markedly reduced when it is left standing for 1 month at 40 °C.
  • The present invention has been made for improvement in this respect and is aimed at provision of a use of a stabilizer effective for preventing decomposition of FK409 and having its pharmacological activity kept for a long period. Another object of the present invention is provision of a method of stabilizing FK409 or drugs containing it as the pharmacologically active ingredient.
  • JP-A-60-28923 discloses an organic acid (e.g. stearic acid, palmitic acid, citric acid, tartaric acid etc.) as a stabilizer in a pharmaceutical composition applicable to the oral mucosa.
  • FR-A-2 333 494 discloses a process for stabilising a solution of a derivate of pyrido(3, 2-a)phenoxazine in which ascorbic acid and isoascorbic acid is used as a stabilizer.
  • Martindale, The Extra Pharmacopoeia, 28th Edition, 1992, pages 1281-1282, 1287, and 1653-1657 mentions ascorbic acid and isoascorbic acid as antioxidants for pharmaceutical preparations.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The stabilizer used according to the present invention is characterized in that it comprises one or more of organic acids selected from tartaric acid, stearic acid, ascorbic acid, erythorbic acid and malonic acid and the method of the invention is characterized in that stabilization is attained by mixing the aforementioned stabilizer in drugs containing FK409, and the stability of FK409 as a pharmacological ingredient is markedly improved and FK409-containing drugs excelled in durability of activity are obtained. The present inventors studied various compounds to see their stabilizing effect, that is, to see if they are effective for preventing decomposition of FK409, and as a result discovered that compounds selected from organic acids selected from tartaric acid, stearic acid ascorbic acid, erythorbic acid and malonic acid have excellent stabilization effect. When the above exemplified polycarboxylic acid has an asymmetric carbon atom(s) such as tartaric acid, or malonic acid, each of D-form, L-form or racemic mixture may be used.
  • The salt of FK409 may be pharmaceutically acceptable salt including organic or inorganic salt.
  • As to the quantity of the aforementioned compound to be added as stabilizer, there is no limitation but it is preferred to be not less than 0.1 weight part, more preferably in a range of 0.3-5 weight part, of the quantity of FK409.
  • The drug composition of the present invention can be mixed with organic or inorganic carriers or excipients suited for external, oral or non-oral administration so as to be usable as solid, semisolid or liquid medical preparations containing the effective substance of the invention. The invented effective substance (ingredient) may be mixed with any of the ordinary, nontoxic carriers permitted for medical use and suited for preparation of tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and the like. As such carriers may be cited water, dextrose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium silicate, talc, corn starch, keratin, colloid silica, potato starch and urea in solid, semisolid or liquid form, being suited for drug manufacture, and auxiliaries, stabilizers, thickeners, colorants and aromatics are also usable. It is also possible to use preservatives or bacteriostats for stably maintaining the activity of the drug or its effective ingredient in any given form. The medical composition of the invention is also usable for manufacture of persistent drugs of various forms. It is also possible to use the aforementioned drugs as long lasting drugs of various forms.
  • FK409 is poor in stability when mixed with an excipient for drug manufacture and its activity is lost quickly when the mixture is kept in stock at a high temperature, but its decomposition is markedly prevented when one of the aforementioned compounds is added as stabilizer for the resultant preparation or drug to be highly improved in durability of pharmacological activity.
  • The FK409 content of a drug of the present invention may be determined properly with the stage of the disease the drug is prescribed for and its form, if the desired therapeutic effect could be attained.
  • In applying the drug of the invention to human being, it may be prepared in various forms suited for venous or muscular injection, cutaneous administration as in the case of plaster or suppository or oral administration. The dosage depends on the stage of disease and the age of the patient but, generally, the effective dose of FK409 is approx. 0.1-100 mg/kg a day and normal per-time dose is 10 mg, 50 mg, 100 mg or 250 mg on the average.
    • Example
  • The composition and effect of the drug of the present invention will be specifically described below with reference to the cited example.
  • First the stability of of FK409 when it was kept in a capsule, when it was stored mixed with an excipient and when it was mixed with tartaric acid as stabilizer (the residual percentage of FK409) was studied. In the experiment, however, the individual samples were put in #1 bottles, the filled bottles were then sealed, kept at the predetermined temperature and upon lapse of the predetermined time, the residual percentage of FK409 was measured by the liquid chromatographic method and its proportion to the initial content was determined.
  • The compositions of the individual samples are shown in Table 1 and the results in Table 2.
    Figure imgb0002
    Figure imgb0003
  • As seen from Tables 1 and 2, FK409, either in the form of original powder (recipe No. 1) or mixed with an excipient (recipe No.2), totally loses its pharmacological activity after storage for 1 month at 40 °C , but when a proper dose of tartaric acid is added (as stabilizer), decomposition of FK409 is markedly prevented and its residual percentage is largely increased.
  • Table 3 below is given to show the result of study about various compounds on their stabilizing effect on the original powder of FK409. Table 3
    Stabilizer dose(g) Storage condition and residual (%)
    40 °C 50 °C 60°C 60°C
    1 month 1 month 18 days 7 days
    FK409
    Original powder - 0 0 0 99.3
    DL-Tartaric acid 1 97.2 98.0 88.1 99.0
    Stearic acid 1 99.3 95.2 - -
    Vitamin C 1 97.1 98.3 87.8 99.0
    Erythorbic acid 1 96.3 98.4 83.5 99.8
    DL-Malonic acid 1 98.9 83.5 32.5 90.1
    DL-citric acid anhydride 1 70.1 76.3 - -
    The dose of stabilizer in g is per 1 g of the original powder of FK409.
  • As is apparent from Table 3, the compounds used in this experiment all have excellent stabilizing effect on FK409, DL-tartaric acid, stearic acid, vitamin C and erythorbic acid in particular.
  • The storage conditions in this experiment are rather severe ones, one month of storage at 50°C being equivalent to storage at the room temperature for approx. 12 months and, this taken into consideration, the effect of this invention is truly outstanding.
  • Then, the stabilizing effect of tartaric acid on tablets with FK409 as active ingredient will be demonstrated.
  • The ingredients in the recipe shown Table 4 except only magnesium stearate were mixed, 40 ml of water was added to the mixture (approx. 135 g) and the wetted mixture was uniformly kneaded, vacuum dried and granulated. To the granules the prescribed amount of magnesium stearate was added and, after mixing, the mixture was made into tablets 7mm in diameter by the use of a tablet making machine.
  • 40 tablets thus obtained were put in a #3 bottle, the filled sealed bottle was stored for the predetermined period at the room temperature (25°C ) or 40 °C , and then the residual percentage of FK409 was studied.
  • The result was as shown in Table 5, and from the tabulated data it is apparent that tartaric acid has an excellent stabilizing effect on FK409 even when it is prepared in tablet form. Table 4
    Recipe No. 1 2 3 4
    Composition (mg) FK409 (Pharma. ingredient) 10 40 10 40
    DL-Tartaric acid (stabilizer) 3 12 3 12
    D-Mannit 107.95 68.95 107.95 68.95
    ECG 505 12 12 - -
    Ac-Di-So1 - - 12 12
    TC-5E 1.35 1.35 1.35 1.35
    Magnesium stearate 0.7 0.7 0.7 0.7
    Total 135 135 135 135
    ECG 505: Carboxyl methyl cellulose calcium (disintegrator)
    Ac-Di-So1: Crosslinked-carboxyl methyl cellulose-sodium (disintegrator)
    TC-5E: Hydroxy propyl methyl cellulose (binder)
    Magnesium stearate (lubricant)
    Table 5
    Residual percentage (%)
    Recipe 1 Recipe 2 Recipe 3 Recipe 4
    Initial 100.0 100.0 100.0 100.0
    Storage condition 40 °C 1 month 98.9 100.0 99.9 100.0
    6 months 96.8 97.3 95.1 95.8
    Room temp. 1 month 100.0 99.9 99.3 100.0
    6 months 99.2 99.8 99.3 99.6

Claims (4)

  1. A stabilizing method for a compound represented by the following chemical formula (I)
    Figure imgb0005
     or a salt thereof acceptable as a drug, wherein as stabilizer an organic acid selected from the group of tartaric acid, stearic acid, ascorbic acid, erythorbic acid and malonic acid is mixed with a compound represented by said chemical formula (I) or a salt thereof accepted as drug.
  2. A stabilizing method according to claim 1, wherein said compound represented by the chemical formula (I) is (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide.
  3. A stabilizing method according to claim 1 wherein the quantity added of said stabilizer is not less than 0.1 weight part is mixed with 1 weight part of said compound represented by said chemical formula (I) or a salt thereof accepted as drug.
  4. A stabilizing method according to claim 3 wherein the quantity added of said stabilizer is 0,3-5 weight part.
EP91104502A 1990-03-28 1991-03-22 Stabilizer for 4-ethyl-2-hydroxyimino5-nitro-3-hexenamide-containing preparation and stabilizing method therefor Expired - Lifetime EP0452697B1 (en)

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JP81790/90 1990-03-28
JP8179090 1990-03-28
JP21305190 1990-08-10
JP213051/90 1990-08-10

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EP0452697A1 EP0452697A1 (en) 1991-10-23
EP0452697B1 true EP0452697B1 (en) 1995-12-06

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6489346B1 (en) 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6645988B2 (en) 1996-01-04 2003-11-11 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US8815916B2 (en) 2004-05-25 2014-08-26 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

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JPS5270014A (en) * 1975-12-05 1977-06-10 Senju Pharma Co Stabilization of pyrido*3*22a*phenoxadine compounds
ZA838831B (en) * 1982-12-31 1984-07-25 Fujisawa Pharmaceutical Co New nitro aliphatic compounds,process for preparation thereof and use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Martindale The Extra Pharmacapoeia, 28th edition, 1982, pages 1281-1282, 1287 and 1653-1657 *
The Merck Index, 11th edition, 1989, pages 867 and 1093 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6489346B1 (en) 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6645988B2 (en) 1996-01-04 2003-11-11 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8815916B2 (en) 2004-05-25 2014-08-26 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

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CA2038716A1 (en) 1991-09-29
AU7381591A (en) 1991-10-03
JPH04217915A (en) 1992-08-07

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